tbuckley/cabot-search huggingface dataset:
FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, <i>HER2</i>-Positive <i>RAS</i> Wild-Type Colorectal Cancer
Authors: Sandra J. Casak, M. Naomi Horiba, Mengdie Yuan, Joyce Cheng, Steven J. Lemery, Yuan Li Shen, Wentao Fu, Jason N. Moore, Yangbing Li, Youwei Bi, Doris Auth, Nataliya Fesenko, Paul G. Kluetz, Richard Pazdur, Lola A. Fashoyin-Aje
Journal: Clinical Cancer Research (2023)

Abstract On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28–49] and median DOR was 12.4 months (95% CI: 8.5–20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6–7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.
Abstract 11659: Comparing Rates of Acute Myocardial Infarction Between Cancer Therapies in Patients With Non-Small Cell Lung Cancer
Authors: Ahmed Abdelhamid, Saket Girotra, Heidi Ferguson, Mary S Vaughan Sarrazin
Journal: Circulation (2022)

Introduction: The prevalence of cardiovascular disease (CVD) has increased in patients with cancer, contributing significantly to mortality among cancer survivors. Cardiotoxicity of anti-cancer drugs may play a role in the development of CVD among cancer survivors, including incidence of acute myocardial infarction (AMI). We analyzed AMI rates in patients with non-small cell lung cancer (NSCLC) treated with one of four cancer regimens. Methods: We used national data from the Veterans Affairs (VA) Corporate Data Warehouse and VA Cancer Registry. We identified 9,619 veterans diagnosed with NSCLC during 2015-2019 who initiated one of four oncological therapies: chemotherapy, immune checkpoint inhibitors (ICI) with chemotherapy, ICI monotherapy, or tyrosine kinase inhibitors monotherapy (TKI). Patients were categorized according to the first therapy received. We identified subsequent hospitalizations for AMI within two years of initiating the oncological treatment. We estimated AMI rates per 100 patient-years and risk adjusted relative hazard ratio (HR) of AMI by treatment type using Cox Regression Model to adjust for age, AMI history, comorbidities, malignancy stage, and histology. Results: Among 9,618 veterans identified, 5,510 (57.3%) initiated treatment with chemotherapy, 2,820 (29.3%) ICI with chemotherapy, 829 (8.6%) with ICI monotherapy, and 459 (4.8%) with TKI. Over a follow-up period of 2 years, 158 (1.6%) patients experienced an AMI and 5,917 (61.5%) died. The incidence of AMI per 100 patient-years (95% CI) was as follows; chemotherapy 0.86 (0.70-1.06), ICI with chemotherapy 0.77 (0.58-1.03), ICI monotherapy 0.91 (0.52-1.60), and TKI 0.43 (0.16-1.15). When compared to chemotherapy alone, adjusted HR (95% CI) for ICI with chemotherapy, ICI monotherapy, and TKI were 1.09 (0.91-1.31), 1.02 (0.75-1.38), and 1.50 (0.94-2.37), respectively. When compared to TKI or ICI with chemotherapy, the ICI monotherapy cohort did not have a statistically significant adjusted HR for AMI risk. Conclusion: Among Veterans with NSCLC, the incidence of AMI was low and there was no difference in risk between the initial oncological regimens. The high competing risk of mortality in our cohort may also have contributed to the lack of between-group differences.
Abstract 11283: Induction of Interferon-Stimulated Gene 15 by Pressure Overload Facilitates Adverse Ventricular Remodeling
Authors: Veera Ganesh Yerra, Sri Nagarjun Batchu, Harmandeep Kaur, MD Golam Kabir, Youan Liu, Suzanne Advani, Shadi Sadeghian, Phelopater Sedrak, Filio Billia, Uros Kuzmanov, Anthony Gramolini, Kim Connelly, Andrew Advani
Journal: Circulation (2022)

Introduction: Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how cardiomyocytes respond to accumulating inflammatory cells within the remodeling heart and how this response, in turn, affects heart function. Methods: Experiments were performed in mouse and rat models of pressure overload, cultured mouse and human cardiomyocytes and human heart failure tissue. Results: CCR2+ monocyte-derived macrophages from Ccr2 gfp/+ mice accumulated early in mouse hearts after transverse aortic constriction (TAC) and Ccr2 knockout attenuated cardiac function decline (ejection fraction, fractional shortening, cardiac output and stroke volume). Cardiomyocyte RNA sequencing revealed that the secretome of CCR2+ cells isolated from TAC hearts induced an interferon response in cardiomyocytes, characterized by upregulation of interferon-stimulated gene 15 (ISG15), which post-translationally modifies actively translated proteins through a process termed ISGylation. ISG15 upregulation or protein ISGylation were also observed in the hearts of mice infused with angiotensin II, uninephrectomized rats treated with DOCA-salt, rats after pulmonary artery banding; mouse and human cardiomyocytes exposed to recombinant interferons; and ventricular tissue of humans with non-ischemic cardiomyopathy. ISG15 accumulated at, or close to, cardiomyocyte intercalated discs and Nano LC-MS/MS, co-immunoprecipitation and co-localization experiments identified the myofibrillar protein filamin-C to be an ISGylation target at these sites. Lastly, knockout of Isg15 attenuated cardiac function decline in mice following TAC, accompanied by a transcriptional profile indicative of preserved cardiac energetics. Conclusions: Collectively, these studies reveal that ISG15 induction is a characteristic of non-ischemic ventricular remodeling and they identify protein ISGylation as an inflammation-induced post-translational modification that may contribute to heart failure development. Strategies that prevent the ISGylation of cardiomyocyte proteins occurring during ventricular remodeling may improve heart failure outcomes.
Abstract 11202: A Biomarker of Stress and Self-Reported Stress Related to Caregiving Predict Poor Quality of Life in Caregivers of Patients With Heart Failure
Authors: Tsuey-yuan Huang, Ming-Fen Tsai, Chin-Yen Lin, Misook L Chung
Journal: Circulation (2022)

Introduction: Caregivers of patients with heart failure (HF) are at high risk of low quality of life due to stress-related to caregiving. Self-reported measures are commonly used to assess relatively long-term stress related to caregiving. Still, biological markers of stress, a short-term stress measure, are rarely used. There is limited knowledge on whether both can predict the quality of life in caregivers of patients with HF. Hypothesis: The stress biomarker (serum cortisol) and subjective distress related to caregiving (Caregiver Burden Inventory) predict the quality of life in caregivers of patients with HF. Methods: In this cross-sectional study, Taiwanese caregivers of patients with HF completed surveys including stress-related caregiving and quality of life measured by the Caregiving Burden Inventory and the Short Form-36, respectively. A blood sample for serum cortisol was collected between 9 and 12 AM. Independent t-test and multivariable linear regression analysis were conducted adjusting for age, gender, education, marital status, relationship with care-recipient and depressive symptoms (Patient Health Questionnaire). Results: Of the 113 caregivers (mean age 54.5 years, 70.8% female, 78% married/cohabitated), 59% cared for patients with NYHA class III/V. Single caregivers had higher serum cortisol levels than married caregivers (11.4 vs. 8.5, p =.002). Males had a significantly higher serum cortisol level than females (10.7 vs. 8.5, p =.010), but males reported a lower caregiver burden than females (1.3 vs. 1.6, p =.049). Both serum cortisol (β =-.36, P=.012) and caregiver burden (β = -.29, P= .018) were significant predictors of physical well-being. Serum cortisol (β= -.28, p=.026) and caregiver burden (β =-.25, p =.027) also significantly predicted mental well-being. Conclusions: Although stress levels are different by caregivers’ characteristics, both cortisol level and self-report caregiver burden have similar predictability of quality of life in caregivers of patients with HF. Reducing stress and caregiver burden is necessary to improve the quality of life in this population.
Abstract 11359: Safety and Efficacy of DOACs Compared to Vitamin K Antagonist in the Treatment of Left Ventricular Thormbus
Authors: Ahmed K Pasha, Muhammad U Siddiqui, Alexander Anzelmi, Altif Muneeb, Keyoor Patel, Alon Yarkoni, Robert D McBane
Journal: Circulation (2022)

Introduction: The Safety and efficacy of DOACs is unknown in patients with left ventricular thrombus as these patients were excluded from DOAC trials. Hypothesis: The safety and efficacy of DOACs is comparable to vitamin K antagonists Methods: Databases including Medline, Scopus and Cochrane Central Registration of Controlled Trials were queried from inception to March 30 th 2022. Studies reporting efficacy and safety outcomes were selected for the analysis. Results: We included 11 studies comprising 1920 patients with left ventricular thrombus. The mean age in the DOAC group was 57.5 years (SD 12.8) and 58.6 years (SD 13.0) in the VKA group; 26.8% were females. Pooled results showed no difference in mortality (RR, 0.64 [95% CI, 0.16-2.52]) embolic events (RR, 0.94 [95% CI, 0.59-1.50]) or major bleeding (RR, 0.95[95% CI, 0.66-1.36]) in the DOACs compared to VKA groups. Event rate for DOAC group compared to VKA group was 12.7 vs 17.5 per 100 patient-years (mean follow up of 4.0 months) for mortality, 19.5 vs 26.5 per 100 patient-years (mean follow up of 8.9 months) for embolic events and 8.0 vs 10.0 per 100 patient-years (mean follow up of 9.5 months) for major bleeding. Conclusions: These data, from observational and randomized studies, demonstrate promising safety and efficacy of DOACs for treatment of left ventricular thrombus. Elevated embolic and mortality rates regardless of anticoagulant choice emphasize the need for further research to improve outcomes for patients with this complication.
Abstract 11555: Risk Factors Associated With Pacemaker Implant Following Hospital Discharge, Within 30 Days of TAVR
Authors: Jessica Cao, Graham Peigh, Jessica Charron, Eric Cantey, James Flaherty, Laura Davidson, S. Christopher Malaisrie, Nishant Verma, Rachel Kaplan
Journal: Circulation (2022)

Introduction: Delayed conduction abnormalities can occur after transcatheter aortic valve replacement (TAVR) in a small but significant group of patients and may be associated with out-of-hospital adverse events including syncope and need for urgent permanent pacemaker (PPM) implantation. There are limited data on the factors associated with need for PPM implantation following TAVR hospital discharge. Methods: A single-center retrospective analysis of TAVR patients (2011-2019) was performed. Exclusion criteria included presence of a PPM prior to TAVR, PPM implant during index admission for TAVR, and absence of pre-TAVR ECG data. The primary endpoint was PPM implantation occurring after hospital discharge, within 30 days of TAVR (late PPM). Results: Of 1148 TAVR procedures performed during the study period, 850 (79.7 ± 9.3 years old, 53.8% male) were included in analysis. There were 16 patients (1.88%) who required late PPM implantation. The median duration of time between discharge and late PPM was 4 (2.8-9.3) days. Univariate analysis revealed that pre-existing right bundle branch block, and change in PR interval from pre-TAVR through day of discharge was associated with late PPM (Figure). Notably, new left bundle branch block was not associated with late PPM. Multivariate analysis demonstrated that change in PR interval from pre-TAVR through day of discharge was independently associated with late PPM. The rate of late PPM increased linearly with greater PR prolongation (y=1.10x-1.01, r2=0.93), and patients with PR increase &gt;20ms had a 4.8% rate of late PPM implantation (Figure). Conclusions: PR prolongation through day of discharge independently predicted need for late PPM following TAVR in our single center experience. Patients with PR increase &gt;20ms from baseline are at particularly high risk for late PPM and should be counseled about the potential need for future PPM.
Abstract 11607: In-Hospital and Readmission Outcomes With Percutaneous Balloon Mitral Valvuloplasty
Authors: Nicole Chahine, Akshay Malhotra, Fizza Hussain, Ahmed Elkaryoni, Amgad Mentias, Mohamad Alkhouli, Paul Gordon, Barry Sharaf, Herbert D Aronow, John J Lopez, Jinnette D Abbott, Marwan S Saad
Journal: Circulation (2022)

Introduction: Percutaneous balloon mitral valvuloplasty (PBMV) is primarily performed for rheumatic mitral stenosis (MS). Therefore, limited data exist on PBMV in countries with a low incidence of rheumatic disease. We sought to examine in-hospital and readmission outcomes for PBMV in the U.S. Methods: Using the Nationwide Readmission Database, hospitalizations in which patients received PBMV for rheumatic and non-rheumatic MS were identified. In-hospital mortality and 30-day readmission rate were examined, and multivariable logistic regression was performed for risk adjustment. Additionally, McNemar's test was used to examine the change in 90-day hospitalization rate before vs. after PBMV. Results: Between 2016-2019 there were 1109 hospitalizations in which patients received PBMV for rheumatic (n= 955, 86.1%) vs non-rheumatic MS (n=154, 13.9%) (Figure). In-hospital mortality (odds ratio (OR) 0.67, 95% confidence interval (CI): 0.19-2.25; p=0.52) and 30-day all-cause readmission rate (OR 1.05, 95% CI: 0.54-2.04; p=0.88) were similar with rheumatic vs non-rheumatic MS, respectively. There was no change in 90-day all-cause hospitalization rate after PBMV for rheumatic and non-rheumatic MS (25.5% to 21.8%; p=0.14, and 24.0% to 33.7%; p=0.19, respectively), and similarly among key subgroups except for male and patients &lt;65 years old; (27.7% to 18.1%, p=0.05) and (26.4% to 20.8%, p=0.05) respectively (Figure). Notably the 90-day heart failure-hospitalization rate significantly decreased after PBMV (16.9% to 12.0% [relative reduction 28.9%], p=0.01). Conclusions: Patients who received PBMV for rheumatic and non-rheumatic MS had similar in-hospital mortality and 30-day all-cause readmission rates. There was no change in the 90-day all cause hospitalization rate before and after PBMV however the 90-day heart failure-hospitalizations were significantly reduced. Future studies are needed to examine the role of PBMV in patients without rheumatic MS.
Abstract 11222: Differential Perivascular Adipose Response to Metabolic Challenge Leads to Sexually Dimorphic Cardiovascular Impairment in Early Prediabetes: Possible Role of Estrogen
Authors: Haneen Dwaib, Nahed Mougharbil, Omar Obeid, Ahmed El-Yazbi
Journal: Circulation (2022)

Cardiovascular (CV) risk associated with metabolic dysfunction commences in early stages preceding the emergence of diagnostic markers. In this regard, a protective role of female sex hormones has been observed where males and postmenopausal females are at a higher risk of these complications. Our previous work on non-obese insulin resistant male rats revealed a crucial role for perivascular adipose tissue (PVAT) inflammation in developing CV dysfunction in early prediabetes. This resulted from PVAT hypoxia evoked by increased uncoupling protein 1 (UCP1) expression and adipocyte hypertrophy in response to a dietary metabolic challenge of mild hypercaloric (MHC) feeding . Here, we examined whether estrogen modulated MHC-induced PVAT dysfunction and its CV consequences. Male and female Sprague-Dawley rats (4-5weeks) were randomly allocated into 2 dietary groups: control or MHC diet for 24 weeks. To control for estrogen effect, bilateral ovariectomy was performed on female rat sub-groups after 12 weeks of feeding with or without daily treatment with an oral dose of 17 β -estradiol (E2) of 2.8 μg/ 100 gm of body weight for an additional 12 weeks. Daily food intake, body weight, body composition, blood glucose and insulin levels, echocardiographic parameters, and blood pressure were measured. At week 24; rats were catheterized for invasive hemodynamic examination. Cardiac autonomic neuropathy was assessed by measuring baroreceptor sensitivity using the vasoactive method. After sacrifice, aortic contractility and endothelial function were examined and molecular investigation were performed. Indeed, the absence of endogenous E2 seemed to precipitate an obese phenotype in MHC-fed female rats and instigate CV impairment together with hallmarks of early PVAT dysfunction reminiscent of those observed in male rats. Intriguingly, E2 replacement restored the protective phenotype observed in intact females. E2 treatment mitigated PVAT inflammation without affecting UCP1 expression levels possibly suggesting a direct anti-inflammatory role. Our results present a novel framework for the protective role of E2 interrupting the inflammatory machinery in PVAT, as well as the subsequent CV dysfunction in presence of a dietary metabolic challenge.
Abstract 11195: Transcatheter versus Surgical Aortic Valve Replacement Outcomes Among Solid Organ Transplant Patients: A Systematic Review and Meta-Analysis
Authors: Vikash Jaiswal, Kriti Kalra, Angela Ishak, Abdelrahman Attia, prachi sharma, Akash Jaiswal, Kendra J Grubb
Journal: Circulation (2022)

Introduction: The safety and clinical outcomes of transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) among solid organ transplant patients are not well documented. Objective: This study aimed to evaluate the clinical outcomes of TAVR and SAVR among patients with a history of solid organ transplantation. Method: We performed a systematic literature search of databases for relevant articles from inception until April 20, 2022. Result: A total of 342 studies were identified, resulting in 7 studies with a total of 6,128 patients included in the final analysis. The odds of in-hospital mortality (OR 0.29, 95% CI 0.16-0.52, p &lt; 0.0001), blood transfusion (OR 0.30, 95% CI 0.22-0.40 p &lt; 0.00001), postoperative bleeding (OR 0.40, 95% CI 0.33-0.48 p &lt; 0.00001), acute kidney injury (OR 0.50, 95% CI 0.38-0.67 p &lt; 0.00001), and sepsis or infection (OR 0.37, 95% CI 0.25-0.56, p &lt; 0.00001) were significantly lower in patients undergoing TAVR compared to SAVR. Permanent pacemaker implantation was significantly higher in patients who underwent SAVR (OR 2.96, 95% CI 1.98-4.44, p = &lt;0.00001) than those who had TAVR. The odds of 30-day mortality, one-year mortality and acute myocardial infarction were similar between the two groups respectively. Length of hospital stay was significantly lower in patients undergoing TAVR (MD -4.12 mmHg, 95% CI -5.06--3.18, p = &lt;0.00001) compared to those who underwent SAVR. Conclusion: TAVR is confirmed to be advantageous in short term with improved in-hospital survival and lower rates of major complications
Abstract 11484: Upregulation of Dynamin 2 Increases Mitochondrial Fission and Cell Proliferation in Pulmonary Arterial Hypertension
Authors: Asish Das Gupta, Kuang-Huieh Chen, Danchen Wu, Jeffrey Mewburn, Patricia Lima, Ruaa Al-Qazazi, Ashley Martin, Lian Tian, Stephen L Archer
Journal: Circulation (2022)

Introduction: The obstructive vasculopathy in pulmonary arterial hypertension (PAH) results in part from acquired mitochondrial changes in pulmonary arterial smooth muscle cells (PASMC), including increased mitotic fission. Mitotic fission, mitochondrial division which is coordinated with mitosis to equitably distribute mitochondria to daughter cells, is mediated by activation of dynamin-related protein 1 (Drp1). To complete mitochondrial fission, Drp1 requires assistance from the GTPase dynamin 2 (DNM2). Hypothesis: Pathological increase in DNM2 expression drives mitochondrial fission and proliferation of PAH PASMC. Methods: Immunoblots of human PASMC and immunohistochemistry and immunofluorescence of lung sections from human (n=5/group) and monocrotaline (MCT) rats with PAH (n=4-5/group) were used to assess the expression of DNM2. The effect of manipulating DNM2 on cell proliferation, cell cycle and apoptosis were assessed by flow cytometry. Mitochondrial fission was quantified using confocal imaging. Results: DNM2 protein expression is increased in human PAH PASMC. DNM2 is also increased in the media of small pulmonary arteries of PAH patients and MCT-PAH rats. Silencing DNM2 inhibited mitochondrial fission and reduced proliferation causing cell cycle arrest in G1/G0 phase. Silencing DNM2 in PAH PASMC also induced apoptosis. Conversely, augmenting DNM2 in normal PASMC induced mitochondrial fission and accelerated cell proliferation. miR-124-3p, a putative negative regulator of DNM2, is decreased in PAH PASMC. Augmenting miR-124-3p decreased DNM2 expression, inhibited proliferation and induced apoptosis in PAH PASMC. Conclusion: In health, DNM2 regulates mitochondrial fission whilst in disease, epigenetic upregulation of DNM2 increases mitotic fission, which drives pathologic proliferation and apoptosis resistance. The miR-124-3p-DNM2 pathway offers novel PAH therapeutic targets.
Abstract 11245: Trends in Cardiovascular Risk Factors Among Women Veterans
Authors: Ramin Ebrahimi, Mei Leng, Annie L Shroyer
Journal: Circulation (2022)

Introduction: Women Veterans (WV) have been identified as a high-risk population for developing ischemic heart disease (IHD). Trends for prevalence of IHD risk factors for WV over the past two decades is unknown. The goal of this study was to evaluate these trends. Methods: Veterans Affairs (VA) electronic health records were used to identify WV aged ≥18 years who visited any VAs nationwide from 1/1/2001-12/31/2017. Risk factors studied included diabetes, hypertension, hyperlipidemia, smoking, and obesity. Prevalence of each risk factor was calculated based on the number of patients alive, and of those, the number of patients with the specific risk factor on December 31 st of each year. Diagnosis of each risk factor was based on the International Classification of Disease versions 9 and 10 codes. Results: Table 1 reveals the prevalence of each risk factor from 2001-2017. During this period the prevalence of these risk factors increased by, 28% for hypertension, 67% for diabetes, 71% for obesity, 140% for hyperlipidemia and 178% for smoking. Alarmingly, in 2017, the prevalence of obesity in WV was &gt;43%. Conclusions: The prevalence of each of these cardiovascular risk factors significantly increased from 2001-2017 in WV. Research towards prevention of these risk factors is warranted in this high-risk population.